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Background: Hypertension is a major risk factor for cardiovascular disease (CVD), which is the number one cause of global mortality. The potential use of natural products to alleviate high blood pressure has been demonstrated to exert a cardioprotective effect. Centella asiatica (L.) Urb. belongs to the plant family Apiaceae (Umbelliferae). It contains a high amount of triterpenoid and flavonoid that have antioxidant properties and are involved in the renin-angiotensin-aldosterone system which is an important hormonal system for blood pressure regulation. Objective: This study aimed to investigate the effects of C. asiatica ethanolic extract on blood pressure and heart in a hypertensive rat model, which was induced using oral N(G)-nitro-l-arginine methyl ester (l-NAME). Methods: Male Sprague-Dawley rats were divided into five groups and were given different treatments for 8 weeks. Group 1 only received deionized water. Groups 2, 4, and 5 were given l-NAME (40 mg/kg, orally). Groups 4 and 5 concurrently received C. asiatica extract (500 mg/kg, orally) and captopril (5 mg/kg, orally), respectively. Group 3 only received C. asiatica extract (500 mg/kg body weight, orally). Systolic blood pressure (SBP) was measured at weeks 0, 4, and 8, while serum nitric oxide (NO) was measured at weeks 0 and 8. At necropsy, cardiac and aortic malondialdehyde (MDA) contents, cardiac angiotensin-converting enzyme (ACE) activity, and serum level of brain natriuretic peptide (BNP) were measured. Results: After 8 weeks, the administrations of C. asiatica extract and captopril showed significant (p < 0.05) effects on preventing the elevation of SBP, reducing the serum nitric oxide level, as well as increasing the cardiac and aortic MDA content, cardiac ACE activity, and serum brain natriuretic peptide level. Conclusion: C. asiatica extract can prevent the development of hypertension and cardiac damage induced by l-NAME, and these effects were comparable to captopril.

To investigate the roles of the renin-angiotensin system and blood pressure in cardiac hypertrophy caused by a pressure overload. Cardiac hypertrophy was induced by constricting the abdominal aorta above the renal arteries. After they had been banded, the rats were treated with the lower (1 mg/kg per day) or the higher (10 mg/kg per day) dose of quinapril [an angiotensin converting enzyme (ACE) inhibitor], or the lower (1 mg/kg per day) or the higher (10 mg/kg per day) dose of TCV-116 [an angiotensin II (AngII) AT1 receptor antagonist], for 4 weeks. Then, we measured the mean blood pressure (MBP), body weight, left ventricular weight (LVW), and serum and cardiac ACE activities. The higher dose of quinapril and that of TCV-116 prevented left ventricular hypertrophy and MBP elevation. Both the higher and the lower doses of quinapril reduced the serum and cardiac ACE activities significantly, whereas the higher dose of TCV-116 reduced the cardiac ACE activity and increased the serum ACE activity. The lower dose of quinapril, however, exerted no significant effect on MBP and the LVW:body weight ratio, although it reduced the cardiac and serum ACE activities significantly. There was a significant positive correlation between the MBP and the LVW:body weight ratio regardless of the cardiac ACE activity in data from all groups (r = 0.676, P < 0.0001). Our data indicate the importance of the blood pressure as a determinant of cardiac hypertrophy because inhibition of cardiac ACE activity alone without lowering of the blood pressure is insufficient to prevent cardiac hypertrophy. Our results suggest the presence of other pathways for AngII production not mediated by ACE, or growth factors other than AngII in pressure-overload cardiac hypertrophy.

Effects of isoproterenol (ISO) on the expression of cardiac angiotensinogen mRNA, angiotensin converting enzyme (ACE) activity, and mechanical functions in spontaneously hypertensive rats were investigated. In the acute phase, defined as within 24 h after the subcutaneous injection of ISO 85 mg/kg, cardiac angiotensinogen mRNA was slightly induced, but ACE activity was not. In the subacute phase, defined as within 8 d after ISO treatment on 2 successive d, both angiotensinogen mRNA expression and ACE activity in the heart were markedly induced. ACE activity in serum was not affected by ISO in either phase. In the subacute phase, ISO reduced body weight and blood pressure, increased ventricular weight and calcium content, and impaired cardiac mechanical function. Oral treatment with imidapril (10 mg/kg/d), an ACE inhibitor, 1 h before each ISO treatment and on the following 6 d, improved ventricular hypertrophy, the elevation of the left ventricular end diastolic pressure, the reduction in contractility, and the prolongation of the time constant. Imidapril significantly suppressed both serum and cardiac ACE activity but did not affect cardiac angiotensinogen mRNA expression in the subacute phase. These results indicate that enhancement of cardiac angiotensinogen mRNA and ACE activity is involved in ISO-induced cardiac dysfunction. Imidapril improved ISO-induced cardiac dysfunction, possibly by suppression of the local ACE activity as well as circulating ACE activity.

Nandrolone decanoate determines cardiac remodelling and injury by an imbalance in cardiac inflammatory cytokines and ACE activity, blunting of the Bezold–Jarisch reflex, resulting in the development of hypertension

Cardiac remodeling and angiotensin II-forming enzyme activity of the left ventricle on chronic pressure overload were studied in male Syrian hamsters, whose chymase activity is similar to that of dogs. Pressure overload was achieved by banding at the ascending aorta (aortic stenosis). Echocardiography, histological analysis, and analysis of cardiac angiotensin-converting enzyme and chymase-like activities were performed. At 10 weeks after banding, concentric hypertrophy of the left ventricle was evident. At 20 weeks after banding, the ventricular weight-to-body ratio, cardiac fibrosis, and cardiac chymase-like activity were significantly increased, while cardiac angiotensin-converting enzyme activity was significantly decreased. This suggests that cardiac chymase, compared with cardiac angiotensin-converting enzyme, was activated against the chronic pressure overload and was responsible for the cardiac remodeling through the formation of angiotensin II. Considering the utility of the rodents, the interspecies similarity of the Ang II-forming pathway, and the effect of chymase in the hamsters, the present model is considered useful for studies evaluating the effect of Ang II and chymase in the canine heart with chronic pressure overload.

On high salt intake, Dahl salt-sensitive rats develop cardiac hypertrophy disproportionate to the degree of hypertension. In the present studies, we assessed whether the cardiac hypertrophy induced by high salt depends on the development of hypertension per se, and leads to over-activity of the cardiac renin-angiotensin system (RAS). Cardiac angiotensin converting enzyme (ACE) mRNA and activity, cardiac and plasma angiotensin I and II (AngI, II), as well as plasma renin activity (PRA) were assessed in Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats on high (1370 micromol/g food) or regular salt (120 micromol/g food) diet for 2-5 weeks. Cardiac ACE and hypertrophic response in Dahl S on high salt were also assessed after central blockade of sympathetic hyperactivity and hypertension. In Dahl S rats, ACE mRNA and activity of the left ventricle (LV) increased markedly after 4-5 weeks of high salt diet compared with Dahl S on the control diet and Dahl R on either diet Chronic intra-cerebroventricular treatment with Fab fragments blocking brain 'ouabain' prevented the hypertension by high salt in Dahl S rats but did not affect the salt-induced increases in LV weight or in LV ACE mRNA and activity. On regular salt diet, Dahl S rats demonstrated significantly lower cardiac AngI and AngII than Dahl R rats. However, high salt intake did not cause significant changes in cardiac AngI and II in either strain. On regular salt diet, PRA, plasma AngI and II were all significantly lower in Dahl S versus R. In Dahl S rats, high salt did not cause further decreases of the already low PRA or plasma AngI and II. These data indicate a low activity of both circulatory and cardiac RAS in Dahl S versus R rats. The marked cardiac hypertrophy and increase in cardiac ACE mRNA and activity induced by high salt in Dahl S do not depend on the increase in blood pressure. High salt intake did not increase cardiac AngII in Dahl S, suggesting that the increase in ACE mRNA and activity may be relevant for non-angiotensinergic mechanisms involved in cardiac hypertrophy.

Some studies reported that herbal interventions with Blepharocalyx salicifolius minimized the high blood pressure in animals. Thus the aim of this study was to evaluate the cardiovascular effects of essential oil from the leaves of the plant. Wistar Kyoto (WKY) and Spontaneously Hypertensive Rats (SHR) with 60 days old were subjected to daily injection of essential oil (10 mg/Kg ip.). At the end of 30 days, the animals were anesthetized, the carotid artery was catheterized to hemodynamic measurements and total blood was collected by puncturing. The cardiovascular measurements performed were systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, myocardial contractility parameters, angiotensin converting enzyme (ACE) activity and myosin ATPase. The hearts were dissected for left ventricle removal, the papillary muscle was used to assess myocardial contractility and tissue to myosin ATPase and ACE activity determinations. The oil was obtained by hydrodistillation in a Clevenger apparatus and analyzed by GC‐FID and GC‐MS. Molecular modelling studies were performed on components of essential oil of B. salicifolium and Angiotensin I‐Converting Enzyme (ACE‐I) in order to support the understanding of the biological activity. The project was approved by the Ethics Committee for Animal Use from UNIPAMPA under number 05/2016. We identified 34 compounds in the essential oil, the sesquiterpenes representing the largest fraction of the essential oil with 55.9% of constitution, and the main component was the spathulenol with 11.6%. We observed an antihypertensive effect attributed the decrease in SBP and DBP (12% and 23%) in SHR treated with essential oil. The myocardial contractility parameters evaluated by isometric force, sarcoplasmic reticulum activity, inotropic response to the calcium, assessment β‐adrenergic response and strength of tetanic contractions, and serum ACE activity were not modified by the essential oil treatment. However, the myosin ATPase activity was increased 51.6% in SHR and the cardiac ACE activity was decreased 41.5% in SHR and 49% in WKY. Molecular modelling studies were performed on the four main components of essential oil, such as limoneme, viridoflorol, santoline triene and spathulenol. The data suggest the spathulenol, that was the higher concentration component in essential oil, could be the main compound inducing the of ACE‐I activity inhibition. The results obtained in this study reveal the antihypertensive action of B. salicifolius essential oil in SHR and the potential interaction with Renin Angiotensin System without impairment of cardiac function.Support or Funding InformationPPSUS/FAPERGSThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Beneficial Effects of Angiotensin-Converting Enzyme Inhibition in Adriamycin-Induced Cardiomyopathy in Hamsters

Angiotensin II (Ang II) may regulate the release of components of the renin-angiotensin system in a tissue-specific manner. In order to study: (1) the effect of Ang II on gene expression and tissue levels of angiotensin-converting enzyme (ACE), and (2) the mechanism of the possible Ang II effect, we treated normal rats with Ang II and Losartan, an angiotensin AT1-receptor antagonist. Forty normal rats received Ang II (n = 20) at a rate of 200 ng kg-1 min-1 or 0.9% NaCl (n = 20) subcutaneously for 3 days using osmotic Alzet minipumps. Ten rats in both groups received Losartan (15 mg kg-1 day-1) in their drinking water, while the rest received tap water. ACE activity and mRNA levels were measured from pulmonary, cardiac, and renal tissue. Ang II treatment resulted in significant increases in blood pressure and heart weight as well as an increase in plasma Ang II concentration and a decrease in plasma renin activity. Simultaneous treatment with Losartan reduced the Ang II-induced effects on blood pressure and heart weight, and attenuated the Ang II-induced decrease in plasma renin activity. Pulmonary ACE activity and mRNA levels decreased during Ang II treatment, and these effects were not modified by simultaneous treatment with Losartan. Cardiac and kidney ACE activities and mRNA levels did not change significantly during Ang II treatment, but Losartan increased cardiac ACE activity (and decreased pulmonary ACE activity). The data indicate that Ang II regulates gene expression and activity of ACE in a tissue-specific manner in the rat, an effect probably involving angiotensin receptor subtype(s) different from the AT1-receptor.

Background: Chronic exposure of organophosphate pesticides is an oxidative stress that causes liver and aortic damage. Malondialdehyde (MDA) is a biological marker of oxidative damage to cell lipids membrane. The liver produces insulin growth factor-1 (IGF-1) which stimulates the enzyme nitric oxide synthase (eNOS) to produce vascular nitric oxide (NO). Children who are living in those area may be exposed to pesticide chronically. Objective: The study aims is to determine the relationship between serum MDA and NO level of children living in an area of chronic pesticide exposure.Method: Cross sectional study was conducted to 50 children aged between 8 – 10 years in agriculture areas of Brebes. Serum MDA and NO level was measured at the same time using ELISA method, data were shown on numerical scale. Statistical analysisby Pearson correlation.Result: Fifty children met the criteria, consisting of 30 males (60%) and 20 females (40%). The mean of serum MDA level in males, females, and total subjects were normal 6.03 (3.86) µg/ mL, 5.18 (2.11) µg/ mL, and 5.69 (2.60) µg/ mL, respectively. The mean of serum NO level in males, females, and total subjects were increased 79.42 (50.78) µmol/ L, 68.11 (50.81) µmol/ L, and 74.90 (50.58) µmol/ L, respectively. There was no association between serum MDA and NO level found.Conclusion: Serum NO level of children living in an area of chronic pesticide exposure was higher than normal value. However, there was no association between serum MDA and NO level found.

This paper aimed to unveil the diagnostic values of serum brain natriuretic peptide (BNP), pentraxin 3 (PTX3), and vascular endothelial growth factor (VEGF) in acute pulmonary embolism complicated by pulmonary artery hypertension (APE-PAH) and their correlations with severity of PAH. A total of 153 patients with APE were selected for our study and divided into the PAH and Non-PAH groups according to the measurement of pulmonary artery pressure by echocardiography. Serum BNP levels were measured by chemiluminescence immunoassay, and serum PTX3 and VEGF levels were appraised by ELISA. The predictive values of BNP, PTX3, and VEGF for APE-PAH were evaluated by applying the receiver operating characteristic (ROC) curve. Spearman test was implemented to correlate BNP, PTX3, and VEGF with the severity of PAH. Higher serum levels of BNP, PTX3, and VEGF were observed in the PAH group versus the Non-PAH group (p < .05). ROC curve analysis indicated that BNP, PTX3, and VEGF had acceptable diagnostic value for predicting APE-PAH. Higher serum levels of BNP, PTX3, and VEGF were witnessed in the moderate and severe PAH groups in contrast to the mild PAH group (p < .05), and the levels of these parameters were elevated in the severe PAH group versus the moderate PAH group (p < .05). Spearman correlation analysis signified that serum BNP (r = 0.377), PTX3 (r = 0.488), and VEGF (r = 0.575) levels were positively correlated with the severity of PAH in APE-PAH patients. Serum BNP, PTX3, and VEGF levels are significantly elevated in APE-PAH patients. Serum BNP, PTX3, and VEGF levels are of clinical value in the diagnosis of APE-PAH patients, and serum BNP, PTX3, and VEGF levels are positively correlated with the severity of PAH and can be used as predictors of the severity of PAH.

Brain Natriuretic Peptide in Acute Ischemic Stroke

In addition to the circulating renin-angiotensin system, recent data demonstrate the existence of tissue renin-angiotensin systems that may be important in cardiovascular homeostasis. However, the relative activities of the circulating and tissue renin-angiotensin systems have not been examined previously in pathophysiological states, such as congestive heart failure. The present study was performed to examine the status of plasma and tissue angiotensin converting enzyme (ACE) activities in compensated experimental heart failure induced by coronary artery ligation in the rat. Three groups of male Sprague-Dawley rats were examined: 1) nonoperated rats (NO, n = 5), 2) sham-operated rats (SO, n = 5), and 3) heart failure rats (HF, n = 11). Rats were studied an averaged of 85 days postoperatively. In HF animals, plasma renin concentration and serum ACE activities were not different compared with NO and SO control animals. Cardiac ACE activity was 50% greater in the right ventricle than the interventricular septum in NO and SO rats. Both right ventricular and interventricular septal ACE activity increased approximately twofold in HF animals as compared with NO and SO groups (p less than 0.05). In contrast, pulmonary, aortic, and renal ACE activities were not altered in HF rats compared with control animals. A positive correlation existed between the histopathological size of myocardial infarction and the level of right ventricular ACE activity (r = 0.75, p less than or equal to 0.05). Such a relation between infarct size and either serum or noncardiac tissue ACE activities was not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

ACE (angiotensin-converting enzyme) 2 is expressed in the heart and kidney and metabolizes Ang (angiotensin) II to Ang-(1–7) a peptide that acts via the Ang-(1–7) or mas receptor. The aim of the present study was to assess the effect of Ang-(1–7) on blood pressure and cardiac remodelling in a rat model of renal mass ablation. Male SD (Sprague–Dawley) rats underwent STNx (subtotal nephrectomy) and were treated for 10 days with vehicle, the ACE inhibitor ramipril (oral 1 mg·kg−1 of body weight·day−1) or Ang-(1–7) (subcutaneous 24 μg·kg−1 of body weight·h−1) (all n = 15 per group). A control group (n = 10) of sham-operated rats were also studied. STNx rats were hypertensive (P<0.01) with renal impairment (P<0.001), cardiac hypertrophy (P<0.001) and fibrosis (P<0.05), and increased cardiac ACE (P<0.001) and ACE2 activity (P<0.05). Ramipril reduced blood pressure (P<0.01), improved cardiac hypertrophy (P<0.001) and inhibited cardiac ACE (P<0.001). By contrast, Ang-(1–7) infusion in STNx was associated with further increases in blood pressure (P<0.05), cardiac hypertrophy (P<0.05) and fibrosis (P<0.01). Ang-(1–7) infusion also increased cardiac ACE activity (P<0.001) and reduced cardiac ACE2 activity (P<0.05) compared with STNx-vehicle rats. Our results add to the increasing evidence that Ang-(1–7) may have deleterious cardiovascular effects in kidney failure and highlight the need for further in vivo studies of the ACE2/Ang-(1–7)/mas receptor axis in kidney disease.

Cardiac angiotensin-converting enzyme (ACE) may play an important role in regulating cardiac hypertrophy. Angiotensin II (Ang II) stimulates cardiac hypertrophy as well as the production of extracellular matrix. However, it is still unclear whether Ang II exerts a direct effect on cardiac hypertrophy independent of its effect on blood pressure or the circulating renin-angiotensin system. Although ACE inhibitors and/or Ang II receptor antagonists have regressed cardiac hypertrophy, classic pharmacological experiments cannot exclude the contribution of hemodynamics and the circulating renin-angiotensin system. In vivo gene transfer provides the opportunity of assessing the effects of increased cardiac angiotensin in the intact animal without circulating angiotensin or blood pressure. Therefore, we used a "gain of function" approach to obtain local overexpression of cardiac ACE. Transfection of the human ACE vector into rat myocardium resulted in a significant increase in cardiac ACE activity (P<0.01). More interestingly, morphometry at 2 weeks after transfection revealed a significant increase in the thickness and areas of cardiac myocytes in hearts transfected with the ACE vector (P<0.01). In addition, transfection of the ACE vector also resulted in a significant increase in collagen content (P<0.01). This increase in cardiac hypertrophy was abolished by the administration of perindopril. Local transfection of the ACE vector into the heart did not result in systemic effects such as increased blood pressure, heart rate, or serum ACE activity. In summary, we have demonstrated that increased autocrine/paracrine angiotensin can directly cause cardiac hypertrophy independent of systemic factors and hemodynamic effects. This approach has important potentials for defining the role of autocrine/paracrine substances in cardiovascular disease.